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Development of Enzyme-Linked Immunosorbent Assays for the Detection of Mutagenic Metabolites of the Herbicide Alachlor

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Development of Enzyme-Linked Immunosorbent Assays for the Detection of Mutagenic Metabolites of the Herbicide Alachlor University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations 1896 - February 2014 1-1-1998 Development of enzyme-linked immunosorbent assays for the detection of mutagenic metabolites of the herbicide alachlor. Daniel M. Tessier University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_1 Recommended Citation Tessier, Daniel M., "Development of enzyme-linked immunosorbent assays for the detection of mutagenic metabolites of the herbicide alachlor." (1998). Doctoral Dissertations 1896 - February 2014. 5666. https://scholarworks.umass.edu/dissertations_1/5666 This Open Access Dissertation is brought to you for free and open access by ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations 1896 - February 2014 by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. DEVELOPMENT OF ENZYME-LINKED IMMUNOSORBENT ASSAYS FOR THE DETECTION OF MUTAGENIC METABOLITES OF THE HERBICIDE ALACHLOR A Dissertation Presented by DANIEL M. TESSIER Submitted to the Graduate School of the University of Massachusetts Amherst in partial fullfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY February 1998 Department of Entomology © Copyright Daniel M. Tessier 1998 All Rights Reserved DEVELOPMENT OF ENZYME-LINKED IMMUNOSORBENT ASSAYS FOR THE DETECTION OF MUTAGENIC METABOLITES OF THE HERBICIDE ALACHLOR A Dissertation Presented by DANIEL M. TESSIER Approved as to style and content by: yC A. oLri Peter C. Uden, Member T. Michaej/Peters, Department Head Department of Entomology ACKNOWLEDGEMENTS I thank Professor John M. Clark for directing my dissertation research and for many years of invaluable support and guidance. Professor Nordin, Professor Uden and Professor Yin are acknowledged for their input and willingness to serve on my dissertation committee. Dr. Bruce Hammock of UC Davis provided critical insight into the hapten conjugation strategy. I thank Dr. E. Michael Thurman of the US Geological Survey for providing groundwater samples for the validation aspects of this research. To the gang at the Pesticide Lab; Ray, Andy, Gerry, Jeff, thanks so much for creating a collegial, highly satisfying (if aesthetically decrepit) place to work. Carry on, men. To the Toxicology group; Steve, Jessica, Aiguo, Yoon, Scott, Kosea and the rest of the new Tox Generation, consider the torch passed. Thanks for everything. v ABSTRACT DEVELOPMENT OF ENZYME-LINKED IMMUNOSORBENT ASSAYS FOR THE DETECTION OF MUTAGENIC METABOLITES OF THE HERBICIDE ALACHLOR FEBRUARY 1998 DANIEL M. TESSIER B.S., UNIVERSITY OF MASSACHUSETTS AMHERST M.S., UNIVERSITY OF MASSACHUSETTS AMHERST Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor J. Marshall Clark The herbicide alachlor is one of the most widely used pesticides in the world; over 52 million pounds are applied to U.S. croplands annually. The acetanilide compounds 2- chloro-2',6'-diethylacetanilide (CDA) and 2-hydroxy-2',6'-diethylacetanilide (HDA) are environmental degradative products of alachlor. CDA, HDA and alachlor are ground and surface water contaminants; CDA and HDA are mutagenic in the Salmonella / microsome assay. There is a paucity of data on the environmental fate of CDA and HDA. The development of two competitive enzyme-linked immunosorbent assays (cELISA) for the detection of CDA and HDA is reported. cELISA3 is specific for CDA with a detection range of 0.015 to 10 pg/ml. Solid phase extraction of CDA residues from aqueous samples gives a 1000-fold concentration factor resulting in an effective detection limit of 15 pg/ml. cELISA4 is specific for both CDA and HDA in combination, with a detection range of 0.01 to 10 pg/ml. Solid phase extraction of aqueous samples prior to cELISA analysis results in an effective detection limit of 10 pg/ml. Chloroacetanilide vi herbicides and other alachlor metabolites that may be present in environmental samples do not interfere with the detection of CDA and HDA. cELISA3, cELISA4 and the antisera they are based on provide a means of studying the environmental fate of CDA and HDA through a variety of analytical strategies. TABLE OF CONTENTS Page ACKNOWLEDGEMENTS. v ABSTRACT. vi LIST OF TABLES. xii LIST OF FIGURES. xiii LIST OF ABBREVIATIONS. xvi Chapter I. INTRODUCTION. 1 A. The Herbicide Alachlor. 1 1. Status of Alachlor Use. 1 2. Magnitude and Significance of Environmental Contamination. 1 B. Environmental Metabolism of Alachlor. 3 C. Mutagenicity of Alachlor Metabolites. 7 D. Cross-Reactivity of CDA and HDA Mutagens in Alachlor Immunoassays. 11 E. Utility of an Alachlor Metabolite Immunoassay. 12 II. SYNTHESIS OF HAPTENIC DERIVATIVES FOR THE PREPARATION OF CDA AND HDA IMMUNOGENS. 14 A. Chemicals. 14 B. Apparatus. 14 C. Synthesis of Haptens. 15 1. Synthesis of Hapten C2-CD A. 15 a. 2,6-Diethylaniline-V-ethyl acetate (2). 15 b. 2,6-Diethylaniline-V-acetic acid (3). 18 c. 2-Chloro-2’ ,6’-diethyl(V-acetic acid)acetanilide (4). 18 vm 19 2. Synthesis of Hapten C4-CDA a. 2,6-Diethylaniline-A-ethylbutyrate (5). 1 * b. 2,6-Diethylaniline-iV-butyric acid (6). 22 c. 2-Chloro-2\6’-diethyl(A-butyric acid)acetanilide (7). 22 3. Synthesis of Hapten Phe-CDA. 22 a. 3,5-Diethylphenol (9). 22 b. 3,5-Diethyl-4-nitrosophenol (10). 22 c. 2,6-Diethyl-4-hydroxyaniline (11). 22 d. 2,6-Diethyl-4-[4’-(ethoxycarbonyl)butoxy]aniline (12). 28 e. 2-Chloro-2’,6’-diethyl-4’-[4”-(ethoxycarbonyl) butoxy]acetanilide (13). 2^ f. 2-Chloro-2 ’ ,6’ -diethyl-4 ’ - [4 ” -(carboxylic acid) butoxy]acetanilide (14). 29 D. Preparation of Hapten-Protein Conjugates. 29 1. Preparation of Active Esters of the CD A Haptens. 29 ' a. General method for the formation of active esters. 32 b. Structural confirmation of the active ester of C2-CDA. 32 c. Structural confirmation of the active ester of C4-CDA. 32 d. Structural confirmation of the active ester of Phe-CDA. 33 2. Conjugation of CDA Haptens to Carrier Proteins. 33 a. Conjugation of active esters. 33 b. Conjugation via N-acetyl homocysteinethiolactone. 33 III. DEVELOPMENT OF A COMPETITION ENZYME-LINKED IMMUNOSORBENT ASSAY (cELISA) FOR THE DETECTION OF CDA AND HD A. 39 A. Antibody Production. 39 B. Procedures for Enzyme Immunoassays. 39 C. Competition Enzyme-Linked Immunosorbent Assays (cELISA). 44 1. cELISA 1: Anti-BSA-C2-CDA Antisera. 44 a. Checkerboard assays. 44 b. Competition assays. 44 c. Cross-reactivity to related compounds. 45 IX 2. cELISA 2: Anti-BSA-C4-CDA Antisera 48 a. Checkerboard assays. 48 b. Competition assays. 48 c. Cross-reactivity to related compounds. 48 3. cELISA 3: Anti-BSA-Phe-CDA Antisera. 54 a. Checkerboard assays. 54 b. Competition assays. 54 c. Cross-reactivity to related compounds. 54 d. Assay optimization. 58 i. pH effects. 58 ii. Solvent effects. 61 4. cELISA 4: Anti-BSA-AHT-CDA Antisera. 62 a. Checkerboard assays. 62 b. Competition assays. 62 c. Cross-reactivity to related compounds. 63 d. Assay optimization. 66 i. pH effects. 66 ii. Solvent effects. 66 D. cELISA Validation... 70 1. Solid Phase Extraction of Aqueous Samples. 70 2. Chromatographic Analysis of Aqueous Sample Extracts. 76 3. Correlation of cELISA and Chromatographic Analysis of Aqueous Samples. 75 4. cELISA Analysis of Alachlor-Contaminated Groundwater Samples for CD A. 75 IV. DISCUSSION AND CONCLUSIONS. 82 A. Hapten Design. g2 B. The CDA and CDA/HDA cELISAs.87 C. Conclusions. gq x APPENDICES 91 A. MASS SPECTRA. 92 B. INFRARED SPECTRA. 115 C. 1H NUCLEAR MAGENTIC RESONANCE SPECTRA. 140 BIBLIOGRAPHY. 145 XI LIST OF TABLES Table Pa8e 1. Selected EPA Leaching Criteria and Chemical Parameters for Alachlor.2 2. Hapten Densities of Immunogens and Plate-Coating Antigens. 34 3. Hapten-Carrier Conjugates Used for Immunization and Plate Coating.40 4. Antisera Designations. 40 5. Checkerboard Assay for Antisera RAX1 versus BSA-C2-CDA and HSA-C2-CDA Plate-Coating Antigens. 45 6. Checkerboard Assay for the Detection of BSA-C4-CDA by Antisera RAX5, RAX6 and RAX7. 49 7. Cross-Reactivity (Reported as IC50) of Chloroacetanilide Herbicides to Antiserum RAX7. 49 8. Checkerboard Assay for the Detection of OVA-Phe-CDA by Antisera , RAX10 and RAX11. 55 9. Cross-Reactivity of RAX11 to Chloracetanilide Herbicides and Related Compounds. 58 10. cELISA3 Signal Attenuation Due to the Effect of Solvents on Antibody Binding. 61 11. Checkerboard Assay for the Detection of OVA-AHT-CDA by Antiserum RAX8. 63 12. Cross-Reactivity of Antiserum RAX8 to Chloracetanilide Herbicides and Related Compounds. 66 13. cELISA4 Signal Attenuation Due to the Effect of Solvents on Antibody Binding. 69 14. Recovery of CD A and HD A from Fortified Water Samples by Solid Phase Extraction... 71 15. Analysis of Alachlor-Contaminated Groundwater Samples 77 LIST OF FIGURES Figure Page 1. Environmental degradative products of alachlor. 6 2. Proposed mechanism of action of CD A and HD A as toxic electrophiles 10 3. Synthesis of hapten C2-CDA (4) containing a 2-carbon spacer group attached to the nitrogen moiety. 17 4. Synthesis of hapten C4-CDA (7) containing a 4-carbon spacer group attached to the nitrogen moiety. 21 5. Synthesis of 2,6-diethyl-4-hydroxyaniline. 24 6. Synthesis of hapten Phe-CDA (14) containing a 5-carbon spacer group attached to the aromatic ring. 26 7. Formation of active esters of C2-CDA, C4-CDA and Phe-CDA via N-hydroxysuccinimide... 31 8. Direct coupling of CDA to protein carrier molecules via N-acetyl homocysteine thiolactone (AHT). 36 9. The hapten-carrier conjugates used to immunize rabbits for the production of CDA and CDA / HDA specific antibodies. 38 10. Antibody capture format used for all competition enzyme-linked immuno¬ sorbent assays (cELISA). 42 11. Competitive inhibition of antiserum RAX1 by CDA and alachlor.47 12. Competitive inhibition of antiserum RAX7 by CDA and alachlor.51 Structures of chloroacetanilide herbicides and related compounds tested for cross-reactivity.
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